Myocardial ischemia and infarction are the leading causes of death in diabetes mellitus, and diabetics appear to be particularly sensitive to cardiac ischemia. Accordingly, we will 1) measure and define any mechanisms of increased ischemic sensitivity in the diabetic myocardium, and 2) determine whether they are altered by the type and degree of diabetic control. The pancreatic Beta-cell cytotoxin alloxan will be used in rabbits to induce diabetes mellitus. A rabbit colony with mild, chronic diabetes will be established where no treatment is required for survival. This mild diabetic - no treatment group will be compared to age and weight-matched non-diabetic groups to determine if untreated mild diabetes increases myocardial sensitivity to ischemic injury. The mild diabetic untreated group will then be compared to mild diabetic groups treated with either insulin or tolbutamide to determine 1) if treatment of mild diabetes affects the myocardial sensitivity to ischemia, and 2) if insulin and tolbutamide treatment result in different myocardial effects. Similar comparisons will be made between a more severe, insulin-dependent diabetic group relative to a non-diabetic control group and between insulin-dependent diabetic groups which are maintained in either "poor" or "good" glycemic control with different insulin regimens. During and after transient ischemia and reperfusion isolated perfused rabbit hearts from the diabetic and non-diabetic groups will be assessed for changes in a) contractility, b) diastolic compliance, c) myocardial levels of ATP, creating phosphate, triglyceride, lactate, edema, and calcium, d) coronary arterial vasodilatory function, and e) metabolic-mechanical coupling efficiency. In parallel intact rabbit studies infarct size will be determined 24 hours after a standardized coronary ligation, and subsequent healing and repair of the infarcted myocardium will be assessed from 1 to 60 days post-infarction by measuring resistance to ventricular rupture, scar size, thickness and elasticity, and the amount of active repair as defined by activity of the key collagen synthetic enzymes prolyl hydroxylase and lysyl oxidase as well as by collagen and elastin content and collagen type and cross-link density.